tbuckley/cabot-search huggingface dataset:
Real-world data on outcomes using taxane, trastuzumab, and pertuzumab (THP) in patients with early stage HER2+ breast cancer.
Authors: Harsh Sharma, Jordyn Kreutzfeldt, Tej Mehta, Kiah Farr, Ursa Brown-Glaberman, Pavani Chalasani, Jacklyn Nemunaitis, Jennifer Margaret Segar
Journal: Journal of Clinical Oncology (2022)

e12630 Background: In HER2+ early breast cancer, dual HER2 targeted combination of trastuzumab and pertuzumab with chemotherapy achieved higher rates of pathologic complete response (pCR) and improved long term outcomes. However, the optimal chemotherapy backbone is still under investigation. While neoadjuvant taxane in combination with trastuzumab and pertuzumab (THP) has been investigated in NEOSPHERE, patients received anthracycline-based regimen in the adjuvant setting. We report real-world data on long-term patient outcomes after neoadjuvant THP. Methods: An IRB-approved retrospective chart review at 2 academic centers was conducted using EMR to identify women with stage I-III HER2+ breast cancer who exclusively received neoadjuvant THP between 2013-2020. Clinicopathological characteristics and follow up information were extracted from surgical pathology and medical records. Results: 71 patients met criteria (median, 55 years). At presentation, 56 (79%) patients had stage II - III disease and 45 (63%) were lymph node negative. The majority of tumors were ER+ (43 patients, 61%) and received paclitaxel (46 patients, 65%) as their taxane backbone. pCR was achieved in 40 (56%) patients (Table); 38 (95%) continued with adjuvant HER2 therapy alone; 1 received adjuvant endocrine therapy only and 1 received no further treatment. Of the 31 (44%) patients without pCR, 9 received additional adjuvant chemotherapy in addition to HER2 directed therapy while 18 continued with HER2 therapy alone. During the follow-up period (median 34.7 mo, range 6.8-98.9 mo), 3 patients with lymph node positive disease on presentation had disease relapse. Two of the patients with pCR had local recurrence and one without pCR had distant metastasis (brain, lung). The 2 patients with local recurrence were successfully treated with salvage therapy and remain in remission. The patient with metastatic disease remains alive and on treatment. Conclusions: We showed that a real world HER2+ patient population treated with neoadjuvant THP achieved pCR rates consistent with what has been previously reported. In addition, with a median follow up of ̃ 3 years, only 3 patients had relapse supporting the utility of THP as potential de-escalation treatment in the neoadjuvant setting. Ongoing prospective trials, like NCT03716180, will further confirm the efficacy of this regimen in a prospective setting.[Table: see text]
Cancer-associated fibroblasts in uterine corpus endometrial carcinoma.
Authors: Yingqiang Li, Jie Zhou, Jing Zhang, Ming Liu, Shifu Chen, Yaqiong Liu
Journal: Journal of Clinical Oncology (2022)

e17618 Background: The general role of cancer-associated fibroblasts (CAFs) and their invasive characteristics in Uterine Corpus Endometrial Carcinoma (UCEC) remain unknown. CAFs serve as an important component of the tumor microenvironment and promote tumorigenesis and cancer aggressiveness. Methods: UCEC mRNA data were downloaded from TCGA cBioPortal ( http://www.cbioportal.org/ ). CAF levels were estimated by three algorithms: MCPCOUNTER, XCELL, and EPIC, so three CAF scores were gotten and ranked. Then, the data of CAF scores in each cohort were divided into quarters, and we labeled the sample by upper quartile and lower quartile with “high”, “medium”, and “low”. To mitigate the possible classification error from each estimation method, we defined samples as “high” by at least two methods consistently labeling “high”. Samples labeled with “low” by at least two methods were assigned to the consensual low CAF group. The high and low group were analysis using GSEA software, Survival analysis was performed using the R package “survival”. Results: There were 129, 118 and 280 samples in the high, low and middle CAFs group, respectively. GSEA results showed extensive gene expression differences between the high and low CAF groups. 193 gene sets were significantly enriched at nominal p value &lt; 0.01 in the low group, 869 gene sets were significantly enriched at nominal p value &lt; 0.01 in the high group. In the low group, obvious differences, included lim mammary stem cell up, reactome degradation of the extracellular matrix, bertucci medullary vs ductal breast cancer dn etc. are enriched in the high group. xu akt1 targets 6hr, OUELLET (Gene Set) ovarian cancer invasive vs lmp up etc. are enriched in the low group. OS and PFS survival analysis showed there was no significant difference between these two groups. Conclusions: Our study analyzed the relationship between CAFs with UCEC, CAFs were associated with an immunosuppressive microenvironment. Larger transcriptomic alterations occurred in UCECs with high CAF infiltration, and with AKT, ALCALA APOPTOSIS and SPLICEOSOME pathways prominent in this process. But Survival analysis showed no difference between the two groups.
Histone demethylase KDM4C is a functional dependency in JAK2-mutated neoplasms
Authors: Philipp Ernst, Tina M. Schnöder, Nicolas Huber, Florian Perner, Ashok Kumar Jayavelu, Theresa Eifert, Chen-Jen Hsu, Nuria Tubío-Santamaría, Carl C. Crodel, Martin Ungelenk, Christian A. Hübner, Joachim H. Clement, Andreas Hochhaus, Florian H. Heidel
Journal: Leukemia (2022)

Abstract Mutations of the JAK2 gene are frequent aberrations in the aging hematopoietic system and in myeloid neoplasms. While JAK-inhibitors efficiently reduce hyperinflammation induced by the constitutively active mutated JAK2 kinase, the malignant clone and abundance of mutated cells remains rather unaffected. Here, we sought to assess for genetic vulnerabilities of JAK2-mutated clones. We identified lysine-specific demethylase KDM4C as a selective genetic dependency that persists upon JAK-inhibitor treatment. Genetic inactivation of KDM4C in human and murine JAK2-mutated cells resulted in loss of cell competition and reduced proliferation. These findings led to reduced disease penetrance and improved survival in xenograft models of human JAK2-mutated cells. KDM4C deleted cells showed alterations in target histone residue methylation and target gene expression, resulting in induction of cellular senescence. In summary, these data establish KDM4C as a specific dependency and therapeutic target in JAK2-mutated cells that is essential for oncogenic signaling and prevents induction of senescence.
CD45-positive tumor infiltrating lymphocytes in early-stage hormone-positive, HER2-negative (ER+/HER2-) breast cancer: Correlation with proliferation and prognostic signature scores.
Authors: Mairi Lucas, Zak Kinsella, Claudia Aura Gonzalez, Camille Hurley, Anna Blümel, Joanna Fay, Anthony O'Grady, Verena Murphy, Chowdhury Arif Jahangir, Caoimbhe Burke, Arman Rahman, John Crown, Catherine Margaret Kelly, William M. Gallagher, Darran O'Connor
Journal: Journal of Clinical Oncology (2022)

e12555 Background: Tumour infiltrating lymphocytes (TILs), have been associated in higher responses to treatment and are thought to be a prognostic marker in a number of cancer types. The role of TILs in breast cancer varies depending on the molecular subtype of the disease. In hormone positive, HER2-negative breast cancer, the significance of TILs is less clear, partly due to the paucity of data in this area. We aim to assess overall TILs in early-stage, hormone-positive, HER2-negative (ER+/HER2-) breast cancer and its relationship with proliferation index, Ki67, and the 21-gene recurrence score. Methods: Archival patient tissue samples of early-stage, ER+/HER2- breast cancer from the Irish arm of the TAILORx clinical trial were used. Full-face sections of these tumours were stained with anti-CD45 antibody (DAKA clone M0701) via the automated Leica Bond III system. A watershed cell-detection algorithm from the open-source digital pathology software, QuPath, was fine-tuned to identify true cell objects and positive immune markers. Optimised detection parameters were used to calculate the percentage of overall CD45+ cells (CD45%) within the tumour area. Patient TIL categories were dichotomised into High v Low CD45%, with 10% chosen as the threshold. CD45% was further correlated with proliferation index, clinical data, and 21-gene recurrence score. Results: 409 samples were included in the analysis. The mean CD45% was 5.96, with samples ranging from 0.13 to 78.86. The majority of samples were in the range of 0-10% of CD45% positivity with 89% (n = 367) patients in this category. Stratification of the cohort by 21-gene-recurrence score (RS) into Low, Intermediate and High, showed a statistically significantly high CD45% in patients with a High RS compared to Low RS (p = 0.0015). When divided by recurrence score group, high CD45% trended toward a lower disease free survival (DFS) when compared to low CD45%, with statistical significance found in those in the Intermediate RS chemotherapy treatment arm (p = 0.009). Conclusions: The role of TILs in ER+/HER2- breast cancer is still undefined. While a High RS was associated with a higher percentage of CD45-positive lymphocytes, the impact on recurrence and response to treatment remains unclear. Further studies to assess the role of different tumour infiltrating lymphocyte phenotypes, and the spatial distribution of assessed markers, are needed.
How Placenta Promotes the Successful Reproduction in High-Altitude Populations: A Transcriptome Comparison between Adaptation and Acclimatization
Authors: Deng Wu, Yunao Liu, Wei Chen, Jianming Shao, Pubu Zhuoma, Dexiong Zhao, Yang Yu, Tianzi Liu, Ruoxuan Yu, Yongna Gan, Baima Yuzheng, Yongshu Huang, Haikun Zhang, Xiaoman Bi, Chengcheng Tao, Shujuan Lai, Qiaoxia Luo, Dake Zhang, Hongmei Wang, Pingcuo Zhaxi, Jianqing Zhang, Jie Qiao, Changqing Zeng
Journal: Molecular Biology and Evolution (2022)

Abstract As the best adapted high altitude population, Tibetans feature a relatively high offspring survival rate. Genome-wide studies have identified hundreds of candidate SNPs related to high altitude adaptation of Tibetans, although most of them have unknown functional relevance. To explore the mechanisms behind successful reproduction at high altitudes, we compared the placental transcriptomes of Tibetans, sea level Hans (SLHan), and Han immigrants (ImHan). Among the three populations, placentas from ImHan showed a hyperactive gene expression pattern. Their increased activation demonstrates a hypoxic stress response similar to sea level individuals experiencing hypoxic conditions. Unlike ImHan, Tibetan placentas were characterized by the significant up-regulation of placenta-specific genes, and the activation of autophagy and the tricarboxylic acid (TCA) cycle. Certain conserved hypoxia response functions, including the antioxidant system and angiogenesis, were activated in both ImHan and Tibetans, but mediated by different genes. The coherence of specific transcriptome features linked to possible genetic contribution was observed in Tibetans. Furthermore, we identified a novel Tibetan-specific EPAS1 isoform with a partial deletion at exon six, which may be involved in the adaption to hypoxia through the EPAS1-centred gene network in the placenta. Overall, our results show that the placenta grants successful pregnancies in Tibetans by strengthening the natural functions of the placenta itself. On the other hand, the placenta of ImHan was in an inhabiting time-dependent acclimatization process representing a common hypoxic stress response pattern.
Overcoming barriers to tumor genomic profiling through direct patient social media outreach.
Authors: Seyram Adjoa Doe-Tetteh, Sabrina Yvonne Camp, Jett Crowdis, Anne Marie Noronha, Dalicia Reales, Tina Alano, Agnes Viale, Mark Donoghue, Nicholas D. Socci, Michael F. Berger, Hikmat A. Al-Ahmadie, Samuel Aaron Funt, Darren R. Feldman, Eli L. Diamond, Eliezer Mendel Van Allen, David B. Solit
Journal: Journal of Clinical Oncology (2022)

6532 Background: Tumor genomic profiling is increasingly used to identify actionable genomic alterations as a guide to therapy selection. To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. Methods: Patients were recruited through social media outreach, engagement with disease advocacy groups, or via physician referral, with a focus on recruiting patients with histiocytosis, germ cell tumors and rare pediatric cancers. Tumor and patient-matched germline DNA were analyzed using the MSK-IMPACT targeted sequencing next generation sequencing panel with return of results to patients and their local physicians. Whole exome recapture of MSK-IMPACT DNA sequencing libraries was performed for patients with female germ cell tumors to define the genomic landscape of this rare cancer subtype. Results: 359 cancer patients expressed interest in the Make-an-IMPACT program, of whom 333 were enrolled. Tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quantity and quality for MSK-IMPACT testing. 14 histiocytosis patients have received genomically guided therapy to date, of whom 13 (93%) have had clinical benefit based on local MD response assessment with a mean treatment duration of 16.7 months (range 3-32+). Whole exome sequencing of ovarian GCTs identified a subset with fully haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%), however, 2 ovarian GCTs and squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. Conclusions: Social media outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians where they could be used to guide treatment selection. This can also open the door to diversifying and being able to study the genomic landscape in a diverse cohort.
Willingness to receive an annual COVID-19 booster vaccine in the German-speaking D-A-CH region in Europe: A cross-sectional study
Authors: Jakob Weitzer, Brenda M. Birmann, Ilja Steffelbauer, Martin Bertau, Lukas Zenk, Guido Caniglia, Manfred D. Laubichler, Gerald Steiner, Eva S. Schernhammer
Journal: The Lancet Regional Health - Europe (2022)

Emergence of new coronavirus variants and waning immunity may necessitate regular COVID-19 vaccine boosters, but empirical data on population willingness for regular vaccination are limited.
REGOMUNE: A phase II study of regorafenib plus avelumab in solid tumors—Results of the oesophageal or gastric carcinoma (OGC) cohort.
Authors: Sophie Cousin, Jean Philippe Metges, Carine A. Bellera, Jean Philippe Guégan, Antoine Adenis, Carlos A. Gomez-Roca, Philippe Alexandre Cassier, Antoine Hollebecque, Coralie Cantarel, Lola Jade Palmieri, Michèle Kind, Isabelle Soubeyran, Jean Palussière, Alban Bessede, Antoine Italiano
Journal: Journal of Clinical Oncology (2022)

4060 Background: Combination VEGF and PD-1/PD-L1 axis blockade has shown benefit in various tumors and is emerging as a promising combination strategy. Methods: This is a single-arm open-label multicentric phase II trial assessing the efficacy and safety of regorafenib (R) (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in advanced or metastatic oesophageal or gastric carcinoma (OGC) patients (pts). The primary endpoint was the confirmed objective response rate, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Dec. 2018 and Mar. 2021, 49 pts were enrolled in 6 centers: 33 adenocarcinoma (ADK), 16 squamous cell carcinoma (SCC). Median age was 63.9 (range 33 – 80). Median follow-up was 14.5 months. Median number of previous treatment lines was: 2 (range 1 – 6). 29 (59.2%) pts experienced at least 1 dose modification or treatment interruption due to an adverse event related to treatment. The most common grade 3/4 adverse events were : Hypertension (12.2% of pts), palmar-plantar erythrodysesthesia syndrome (10.2%), and hypophosphatemia (8.2%). No death was related to the treatment. Among the 42 (29 ADK and 13 SCC) pts who had at least one imaging tumor assessment, 8 (19.1%) achieved a partial response, 5 (17.2%) and 3 (23.1%) in the ADK and SCC group respectively. 12 pts (28.6%) demonstrated stable disease and 22 pts (52.3%) had progressive disease. The median PFS and OS were 1.9 months (95%CI 1.8 – 3.5) and 7.5 months (95%CI 4.5 – 15.7) respectively. Conclusions: The R+A combination is associated with encouraging antitumor activity in patients with OGC. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.
PTSD — Seeking the Ghost in the Machine
Authors: Rebecca D Folkerth
Journal: New England Journal of Medicine (2022)

A century after “the war to end all wars,” we continue to find our human community divided by conflict and our military service members at the leading edge. The ghostly scars of shell shock, later termed post-traumatic stress disorder (PTSD), have haunted generations of soldiers, as well as civilian survivors of many types of trauma, since long before the Great War. Despite current societal acceptance of PTSD as a disorder worthy of compassion, diagnostic recognition, and multidisciplinary research, these scars have remained, like ghosts, largely and frustratingly invisible in the sense that little is understood of their cellular basis in . . .
Does previous prostatic surgery affect the accuracy of multiparametric MRI in detecting clinically significant prostate cancer? Results from a single center, high volume series
Authors: F. Pellegrino, A. Stabile, E. Mazzone, G. Sorce, A. Pellegrino, M. De Angelis, L. Nocera, S. Scuderi, F. Barletta, G. Cirulli, M. Picozzi, L. Toneatto, L. Quarta, M. Tutolo, G. Rosiello, A. Larcher, U. Capitanio, F. De Cobelli, A. Esposito, G. Brembilla, S. Shariat, N. Fossati, A. Salonia, F. Montorsi, A. Briganti
Journal: European Urology (2022)
Clinical significance of tumor location for ureteroscopic tumor grading in upper tract urothelial carcinoma
Authors: S. Katayama, B. Pradere, N.C. Grossmann, A.M. Potretzke, S.A. Boorjian, S. Daneshmand, H. Djaladat, J.P. Sfakianos, A. Mari, Z. Khene, D. D’Andrea, E. Kikuchi, K. Fujita, A. Heindenreich, J.D. Raman, M. Roumiguié, F. Abdollah, J. Marcus, A. Breda, M. Fontana, M. Rouprêt, M. Araki, Y. Nasu, S.F. Shariat
Journal: European Urology (2022)
Correction: Association of physical activity intensity and bout length with mortality: An observational study of 79,503 UK Biobank participants
Authors: Louise A. C. Millard, Kate Tilling, Tom R. Gaunt, David Carslake, Deborah A. Lawlor
Journal: PLoS Medicine (2022)

[This corrects the article DOI: 10.1371/journal.pmed.1003757.].
Is there a role for the oncotype DX breast recurrence score genomic assay in estrogen receptor-low positive breast cancer?
Authors: Julia Giordano, Monica McGrath, Beth Harrison, Olga Kantor, Halley Vora, Harold J. Burstein, Sara M. Tolaney, Tari A. King, Elizabeth A. Mittendorf
Journal: Journal of Clinical Oncology (2022)

564 Background: The Oncotype DX Breast Recurrence Score assay is widely used in estrogen receptor (ER)-positive breast cancer patients to help determine the potential benefit of chemotherapy. However, little is known about the value of the test in breast cancer patients who have ER-low positive (1-10%) cancers. The purpose of this study was to determine the potential utility of the Oncotype test for these patients by describing the range of Recurrence Score (RS) results and patient outcomes. Methods: Patients treated between 8/2011-8/2020 for primary non-metastatic breast cancer that was ER-low positive (10%) and HER2-negative in whom tissue from their surgical excision specimen was available to perform the Oncotype DX assay were identified. Clinicopathologic characteristics were abstracted from patient charts, and the RS result was determined. Results: 38 women with ER-low positive breast cancer and available tissue were identified. The median age was 56.5 (range 36-94); 34 patients were Caucasian, 2 Black, 1 Asian and 1 Hispanic. Thirty-seven patients underwent surgery as their initial intervention and 1 received neoadjuvant chemotherapy. The final pathologic anatomic stage was IA in 26 (68.4%), IB in 10 (26.3%) and IIA in 2 (5.3%); the pathologic nodal status was pN0 in 24 (63.2%), pN0i+ in 3 (7.9%), pN1mi in 1 (2.6%), pN1 in 6 (15.8%) and pNx in 4 (10.5%). The average and median RS was 49 with a range of 23-72; only 2 patients had a RS 25. One patient with RS = 24 was a 64yo with pT1cN0 disease who received chemotherapy + endocrine therapy therefore could potentially have been spared chemotherapy based on the RS result and the TAILORx trial data. Six patients had previously had a RS determined on their diagnostic core biopsy (RS = 46, 58, 45, 47, 51 and 52); the RS on their surgical specimen was concordant (RS = 45, 54, 47, 48, 47, and 50). The ER status as determined by the Oncotype DX assay was positive for 8 (21%) patients. Adjuvant therapy included: chemotherapy and endocrine therapy in 13 (34.2%), chemotherapy alone in 13 (34.2%) and endocrine therapy alone in 4 (10.5%). 8 (21.1%) received no adjuvant therapy. After a median follow-up of 40 months (range 3-106), 3 patients have experienced a recurrence; all 3 had received chemotherapy. The 3-year recurrence free survival rate was 97.0% (95% CI: 96.9-97.1%). All 3 of these patients had a local recurrence; 2 also had a distant recurrence which they ultimately succumbed to. The 3-year disease-specific survival rate was also 97.0% (95% CI: 96.9-97.1%). Conclusions: The majority of the patients with low ER+/HER2- breast cancer had RS &gt; 25 suggesting these tumors are high-risk, more similar to ER- disease. The RS result is of limited utility in ER-low positive patients, as these data indicate that most would benefit from chemotherapy.